Becoming a successful researcher in an area that is focused on improving the lives of cancer patients is my long-term career goal. To accomplish this, a research plan has been developed that includes broad-based training in cellular and molecular biology, cancer pharmacology, and data analysis at Georgetown University's Lombardi Cancer Center. It also includes participation in seminars, journal clubs, national workshops and meetings, and interactions with clinicians. The research project is focused on investigating the mechanisms of antiestrogen resistance, which is an important clinical problem in breast cancer. Completion of these specific aims will lead not only to significant advances in breast cancer research, but also provides a strong, balanced foundation for a productive career in breast cancer research. Advanced breast cancer is often an incurable disease. While improvements in overall survival following endocrine therapy are well documented in women with estrogen receptor (ER)-positive breast cancer, both de novo, and acquired resistance to widely used agents (i.e. Tamoxifen) are a major limitation in the successful treatment of ER-positive breast cancer. The transcription factor interferon regulatory factor-1 (IRF1) is a well-established tumor suppressor gene in breast cancer. Treatment with an antiestrogen (AE) increases IRF1 expression, whereas IRF1 is repressed in AE resistant breast cancer cells and no longer induced by AEs. The precise signaling mechanism of IRF1-regulated cell death is unknown; therefore, understanding how IRF1 signals to cell death following endocrine therapy is crucial in order to improve survival and quality of life for thousands of women with breast cancer. We hypothesize that IRF1 regulates ER-positive breast cancer cel fate (through apoptosis and autophagy) primarily by coordinating the balance of proapoptotic and antiapoptotic BCL2 family member activities. Furthermore, breast cancer cells overexpressing a dominant negative IRF1 (dnIRF1) are dependent upon BCL2 activity for their survival and will be sensitized to BCL2 inhibition in vitro and in vivo. Aim 1: We will determine whether IRF1 directly regulates the transcription of specific BCL2 family members in MCF7, LCC1, and LCC9 cells overexpressing IRF1 or dnIRF1 in response to AEs Aim 2: We will determine the functional role of antiapoptotic BCL2 members in the modulation of AE- induced apoptosis and autophagy downstream of IRF1. Aim 3: We will determine the effects of IRF1-mediated cell death through BCL2 family members in vivo and in human breast tumors. IMPACT: Completion of these aims will establish the mechanistic role of IRF1 and its integrated signaling through BCL2 family members in the context of ER-positive breast cancer. The studies will also determine whether induction of IRF1 signaling can improve responsiveness to AEs when combined with a BCL2 inhibitor. PUBLIC HEALTH RELEVANCE: Approximately 70% of all new cases of invasive breast cancer will be ER-positive and, therefore, likely candidates for endocrine therapy. Successful completion of these aims will establish the mechanistic role of IRF1 and its integrated signaling through BCL2 family members in the context of ER-positive breast cancer. Our studies will also determine whether induction of IRF1 signaling can improve responsiveness to AEs and potentially identify novel drug targets in breast cancer by overcoming BCL2-mediated prosurvival signaling.